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Institute of Virology
Department of Hygiene,
Microbiology and Public Health
at Innsbruck Medical University

Peter-Mayr-Straße 4b
A-6020 Innsbruck

Tel.: 0512/9003-71701
Fax: 0512/9003-73701
E-Mail: virologie@i-med.ac.at
Improving therapeutic antibodies
Background:

The complement system as part of the innate immunity is a first line immune defense of the host and activated immediately upon pathogen entry. A main effector mechanism is the induction of complement-mediated lysis (CML) both of which contribute in the destruction of invading pathogens or tumor cells. Beside the induction of antibody-dependent cellular cytotoxicity (ADCC), antibody (Ab)-based therapies takes advantage of complement activation aiming to destroy pathogens or tumor cells by CML. However for most of the Ab-based therapies, the induction CML is far from optimal as many tumors or pathogens have evolved protection mechanisms favoring the resistance against complement. A main protection mechanism is the binding of regulators of complement activation (RCAs). The original function of RCAs is the protection of host cells against CML. Thus, tumor cells and pathogens divert RCAs from their intended use to favor survival in the host. A prominent RCA is factor H (fH). This factor is a serum protein which binds to the surface of the host cells to protect against CML. Tumor cells or pathogens mimic cellular binding motifs on their surfaces and are thus protected against CML similar as the host cells. Thus tumor cells and pathogens can block an important effector function of Ab-based therapies.

Strategy:

We aim to block fH binding specifically to tumor cells or pathogens to induce CML without affecting ADCC. For this we generate constructs consisting of two parts, a therapeutic Ab and a peptide derived from fH. The Ab indices complement activation at the tumor or pathogen site and shuttles the fH-peptide to the area of interest. The fH-derived peptide itself has no enzymatic activity thus cannot block complement activation and CML, but it contains the binding motif of wild type fH. By inhibition fH binding, pathogens and tumor cells are losing one of their most important protection mechanisms against CML and can be eliminated by the complement system. Thus our complement-based constructs improve the effector functions of therapeutic antibodies by kepping ADCC and boosting CML.

Key words:

  • therapeutic antibody
  • complement
  • tumor
  • pathogen
  • lysis

Members:

  • Heribert Stoiber
  • Stefan Demetz
  • Brigitte Müllauer
  • Zoltán Bánki